Quinolinyl-appended chalcones as promising antiproliferative and trypanocidal agents: Synthesis, biological profiling, and further transformation into novel benzo[f]pyrazolo[5,1-a][2,7]naphthyridine and quinoline-pyrido[2,3-d]pyrimidin-2,4-dione hybrids.

An efficient synthetic methodology has been developed for the transformation of readily available quinolinyl-chalcones 2 and their 3-acetylquinoline 1 precursors into novel benzo[f]pyrazolo[5,1-a][2,7]naphthyridine 3 and quinoline-pyrido[2,3-d]pyrimidin-2,4-dione 4 hybrids, respectively, via sequential Claisen-Schmidt condensation, Michael addition, and intramolecular cyclocondensation. This approach successfully incorporated pyrazole, naphthyridine, and pyrido[2,3-d]pyrimidine motifs into the target hybrid scaffolds 3 and 4. Biological evaluation revealed that quinolinyl-chalcones 2 displayed a favorable balance between potency and cytotoxicity, with 2g identified as the most promising lead based on its submicromolar activity in colon, leukemia, and breast cell lines and low intrinsic cytotoxicity. In contrast, hybrids 3 and 4 were inactive in both antitumor and antichagasic assays, indicating that these hybridization approaches are not suitable for further development. Mechanistic studies revealed that quinolinyl-chalcone 2a was the most active trypanocidal agent, acting through oxidative stress induction, thereby highlighting it as a promising scaffold for the design of redox-active antichagasic drug candidates.